Chronic myeloid leukemia (CML) and about 20% of acute lymphoblastic leukemias (ALL) are characterized by expression of the oncogenic fusion protein Bcr-Abl that has constitutive tyrosine kinase activity. The selective Bcr-Abl antagonist imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor that has proven highly effective in the treatment of CML. Although effective, imatinib therapy is usually not curative. Imatinib fails to completely eliminate Bcr-Abl+ cells and the disease often relapses due to development of imatinib resistance. Also, Bcr-Abl+ ALL is refractory to treatment with imatinib. Targeting additional gene products may enhance the efficacy of imatinib in eliminating CML and Bcr-Abl+ ALL cells and lead to complete eradication of disease. We have designed an unbiased loss-of-function screen using RNA interference (RNAi) to identify such genes. We utilized a genome-wide lentiviral small hairpin RNA (shRNA) library in combination with microarray analysis to identify gene targets that, when inhibited, potentiate Bcr-Abl+ cell killing by imatinib. Our screen identified multiple genes that are components of a noncanonical Wnt/calcium signaling pathway whose biological role is poorly understood. We plan to further analyze these genes to determine if their inactivation effectively cooperates with imatinib in killing Bcr-Abl+ cells in vitro and in mouse models of CML and Bcr-Abl+ ALL.